Possible involvement of radical intermediates in the inhibition of cysteine proteases by allenyl esters and amides.
In order to investigate crystallographically the mechanism of inhibition of cysteine protease by alpha-methyl-gamma,gamma-diphenylallenecarboxylic acid ethyl ester 3, a cysteine protease inhibitor having in vivo stability, we synthesized N-(alpha-methyl-gamma,gamma-diphenylallenecarbonyl)-L-phenylalanine ethyl ester 4. Reaction of 4 with thiophenol, the SH group of which has similar pK(a) value to that of cysteine protease, produced oxygen-mediated radical adducts 6 and 7 in ambient air but did not proceed under oxygen-free conditions. Catalytic activities of two thiol enzymes including cathepsin B were also lowered in the absence of oxygen. These results suggest that cysteine protease can act through an oxygen-dependent radical mechanism.
Takeuchi
Yoshio
Y
Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan. takeuchi@pha.u-toyama.ac.jp
Fujiwara
Tomoya
T
Shimone
Yoshihito
Y
Miyataka
Hideki
H
Satoh
Toshio
T
Kirk
Kenneth L
KL
Hori
Hitoshi
H
D000577:Amides / Q000494:pharmacology*; D000818:Animals; D053455:Caspase 10 / Q000378:metabolism; D002384:Catalysis; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004952:Esters; D015394:Molecular Structure; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D000577:Amides; D015853:Cysteine Proteinase Inhibitors; D004952:Esters; D013438:Sulfhydryl Compounds; D053455:Caspase 10; D003546:Cysteine Endopeptidases; D010100:Oxygen